Spinal Sensorimotor Circuits Research Articles

Operation of spinal sensorimotor circuits controlling phase durations during tied-belt and split-belt locomotion after a lateral thoracic hemisection.

Locomotion is controlled by spinal circuits that interact with supraspinal drives and sensory feedback from the limbs. These sensorimotor interactions are disrupted following spinal cord injury. The thoracic lateral hemisection represents an experimental model of an incomplete spinal cord injury, where connections between the brain and spinal cord are abolished on one side of the cord. To investigate the effects of such an injury on the operation of the spinal locomotor network, we used our computational model of cat locomotion recently published in eLife (Rybak et al., 2024) to investigate and predict changes in cycle and phase durations following a thoracic lateral hemisection during treadmill locomotion in tied-belt (equal left-right speeds) and split-belt (unequal left-right speeds) conditions. In our simulations, the "hemisection" was always applied to the right side. Based on our model, we hypothesized that following hemisection, the contralesional ("intact", left) side of the spinal network is mostly controlled by supraspinal drives, whereas the ipsilesional ("hemisected", right) side is mostly controlled by somatosensory feedback. We then compared the simulated results with those obtained during experiments in adult cats before and after a mid-thoracic lateral hemisection on the right side in the same locomotor conditions. Our experimental results confirmed many effects of hemisection on cat locomotion predicted by our simulations. We show that having the ipsilesional hindlimb step on the slow belt, but not the fast belt, during split-belt locomotion substantially reduces the effects of lateral hemisection. The model provides explanations for changes in temporal characteristics of hindlimb locomotion following hemisection based on altered interactions between spinal circuits, supraspinal drives, and somatosensory feedback.

Dual electrical stimulation at spinal-muscular interface reconstructs spinal sensorimotor circuits after spinal cord injury

The neural signals produced by varying electrical stimulation parameters lead to characteristic neural circuit responses. However, the characteristics of neural circuits reconstructed by electrical signals remain poorly understood, which greatly limits the application of such electrical neuromodulation techniques for the treatment of spinal cord injury. Here, we develop a dual electrical stimulation system that combines epidural electrical and muscle stimulation to mimic feedforward and feedback electrical signals in spinal sensorimotor circuits. We demonstrate that a stimulus frequency of 10−20 Hz under dual stimulation conditions is required for structural and functional reconstruction of spinal sensorimotor circuits, which not only activates genes associated with axonal regeneration of motoneurons, but also improves the excitability of spinal neurons. Overall, the results provide insights into neural signal decoding during spinal sensorimotor circuit reconstruction, suggesting that the combination of epidural electrical and muscle stimulation is a promising method for the treatment of spinal cord injury.

Simultaneous control of forward and backward locomotion by spinal sensorimotor circuits.

Mammals walk in different directions, such as forward and backward. In human infants/adults and decerebrate cats, one leg can walk forward and the other backward simultaneously on a split-belt treadmill, termed hybrid or bidirectional locomotion. The purpose of the present study was to determine if spinal sensorimotor circuits generate hybrid locomotion and if so, how the limbs remain coordinated. We tested hybrid locomotion in 11 intact cats and in five following complete spinal thoracic transection (spinal cats) at three treadmill speeds with the hindlimbs moving forward, backward or bidirectionally. All intact cats generated hybrid locomotion with the forelimbs on a stationary platform. Four of five spinal cats generated hybrid locomotion, also with the forelimbs on a stationary platform, but required perineal stimulation. During hybrid locomotion, intact and spinal cats positioned their forward and backward moving hindlimbs caudal and rostral to the hip, respectively. The hindlimbs maintained consistent left-right out-of-phase alternation in the different stepping directions. Our results suggest that spinal locomotor networks generate hybrid locomotion by following certain rules at phase transitions. We also found that stance duration determined cycle duration in the different locomotor directions/conditions, consistent with a common rhythm-generating mechanism for different locomotor directions. Our findings provide additional insight on how left-right spinal networks and sensory feedback from the limbs interact to coordinate the hindlimbs and provide stability during locomotion in different directions. KEY POINTS: Terrestrial mammals can walk forward and backward, which is controlled in part by spinal sensorimotor circuits. Humans and cats also perform bidirectional or hybrid locomotion on a split-belt treadmill with one leg going forward and the other going backward. We show that cats with a spinal transection can perform hybrid locomotion and maintain left-right out-of-phase coordination, indicating that spinal sensorimotor circuits can perform simultaneous forward and backward locomotion. We also show that the regulation of cycle duration and phase duration is conserved across stepping direction, consistent with a common rhythm-generating mechanism for different stepping directions. The results help us better understand how spinal networks controlling the left and right legs enable locomotion in different directions.

Spinal Sensorimotor Circuits Play a Prominent Role in Hindlimb Locomotor Recovery after Staggered Thoracic Lateral Hemisections but Cannot Restore Posture and Interlimb Coordination during Quadrupedal Locomotion in Adult Cats

AbstractSpinal sensorimotor circuits interact with supraspinal and peripheral inputs to generate quadrupedal locomotion. Ascending and descending spinal pathways ensure coordination between the forelimbs and hindlimbs. Spinal cord injury (SCI) disrupts these pathways. To investigate the control of interlimb coordination and hindlimb locomotor recovery, we performed two lateral thoracic hemisections on opposite sides of the cord (right T5–T6 and left T10–T11) at an interval of approximately two months in eight adult cats. In three cats, the spinal cord was transected at T12–T13. We collected electromyography (EMG) and kinematic data during quadrupedal and hindlimb-only locomotion before and after spinal lesions. We show that (1) cats spontaneously recover quadrupedal locomotion following staggered hemisections but require balance assistance after the second one, (2) coordination between the forelimbs and hindlimbs displays 2:1 patterns (two cycles of one forelimb within one hindlimb cycle) and becomes weaker and more variable after both hemisections, (3) left-right asymmetries in hindlimb stance and swing durations appear after the first hemisection and reverse after the second, and (4) support periods reorganize after staggered hemisections to favor support involving both forelimbs and diagonal limbs. Cats expressed hindlimb locomotion the day following spinal transection, indicating that lumbar sensorimotor circuits play a prominent role in hindlimb locomotor recovery after staggered hemisections. These results reflect a series of changes in spinal sensorimotor circuits that allow cats to maintain and recover some level of quadrupedal locomotor functionality with diminished motor commands from the brain and cervical cord, although the control of posture and interlimb coordination remains impaired.

Spinal Cord fMRI: A New Window into the Central Nervous System.

With the brain, the spinal cord forms the central nervous system. Initially considered a passive relay between the brain and the periphery, the spinal cord is now recognized as being active and plastic. Yet, it remains largely overlooked by the human neuroscience community, in stark contrast with the wealth of research investigating the brain. In this review, we argue that fMRI, traditionally used to image cerebral function, can be extended beyond the brain to help unravel spinal mechanisms involved in human behaviors. To this end, we first outline strategies that have been proposed to tackle the challenges inherent to spinal cord fMRI. Then, we discuss how they have been utilized to provide insights into the functional organization of spinal sensorimotor circuits, highlighting their potential to address fundamental and clinical questions. By summarizing guidelines and applications of spinal cord fMRI, we hope to stimulate and support further research into this promising yet underexplored field.

Epidural electrical stimulation to facilitate locomotor recovery after spinal cord injury.

Tonic or phasic electrical epidural stimulation of the lumbosacral region of the spinal cord facilitates locomotion and standing in a variety of preclinical models with severe spinal cord injury. However, the mechanisms of epidural electrical stimulation that facilitate sensorimotor functions remain largely unknown. This review aims to address how epidural electrical stimulation interacts with spinal sensorimotor circuits and discusses the limitations that currently restrict the clinical implementation of this promising therapeutic approach.

The Spinal Control of Backward Locomotion.

Animal locomotion requires changing direction, from forward to backward. Here, we tested the hypothesis that sensorimotor circuits within the spinal cord generate backward locomotion and adjust it to task demands. We collected kinematic and electromyography (EMG) data during forward and backward locomotion at different treadmill speeds before and after complete spinal transection in six adult cats (three males and three females). After spinal transection, five/six cats performed backward locomotion, which required tonic somatosensory input in the form of perineal stimulation. One spinal cat performed forward locomotion but not backward locomotion while two others stepped backward but not forward. Spatiotemporal adjustments to increasing speed were similar in intact and spinal cats during backward locomotion and strategies were similar to forward locomotion, with shorter cycle and stance durations and longer stride lengths. Patterns of muscle activations, including muscle synergies, were similar for forward and backward locomotion in spinal cats. Indeed, we identified five muscle synergies that were similar during forward and backward locomotion. Lastly, spinal cats also stepped backward on a split-belt treadmill, with the left and right hindlimbs stepping at different speeds. Therefore, our results show that spinal sensorimotor circuits generate backward locomotion but require additional excitability compared with forward locomotion. Similar strategies for speed modulation and similar patterns of muscle activations and muscle synergies during forward and backward locomotion are consistent with a shared spinal locomotor network, with sensory feedback from the limbs controlling the direction.SIGNIFICANCE STATEMENT Animal locomotion requires changing direction, including forward, sideways and backward. This paper shows that the center controlling locomotion within the spinal cord can produce a backward pattern when instructed by sensory signals from the limbs. However, the spinal locomotor network requires greater excitability to produce backward locomotion compared with forward locomotion. The paper also shows that the spinal network controlling locomotion in the forward direction also controls locomotion in the backward direction.

The relationship between maximum tolerance and motor activation during transcutaneous spinal stimulation is unaffected by the carrier frequency or vibration.

Transcutaneous spinal stimulation (TSS) is a useful tool to modulate spinal sensorimotor circuits and has emerged as a potential treatment for motor disorders in neurologically impaired populations. One major limitation of TSS is the discomfort associated with high levels of stimulation during the experimental procedure. The objective of this study was to examine if the discomfort caused by TSS can be alleviated using different stimulation paradigms in a neurologically intact population. Tolerance to TSS delivered using conventional biphasic balanced rectangular pulses was compared to two alternative stimulation paradigms: a 5 kHz carrier frequency and biphasic balanced rectangular pulses combined with vibrotactile stimulation. In ten healthy participants, tolerance to TSS was examined using both single‐pulse (0.2 Hz) and continuous (30 Hz) stimulation protocols. In both the single‐pulse and continuous stimulation protocols, participants tolerated significantly higher levels of stimulation with the carrier frequency paradigm compared to the other stimulation paradigms. However, when the maximum tolerable stimulation intensity of each stimulation paradigm was normalized to the intensity required to evoke a lower limb muscle response, there were no statistical differences between the stimulation paradigms. Our results suggest that, when considering the intensity of stimulation required to obtain spinally evoked motor potentials, neither alternative stimulation paradigm is more effective at reducing discomfort than the conventional, unmodulated pulse configuration.

The recovery of standing and locomotion after spinal cord injury does not require task-specific training.

After complete spinal cord injury, mammals, including mice, rats and cats, recover hindlimb locomotion with treadmill training. The premise is that sensory cues consistent with locomotion reorganize spinal sensorimotor circuits. Here, we show that hindlimb standing and locomotion recover after spinal transection in cats without task-specific training. Spinal-transected cats recovered full weight bearing standing and locomotion after five weeks of rhythmic manual stimulation of triceps surae muscles (non-specific training) and without any intervention. Moreover, cats modulated locomotor speed and performed split-belt locomotion six weeks after spinal transection, functions that were not trained or tested in the weeks prior. This indicates that spinal networks controlling standing and locomotion and their interactions with sensory feedback from the limbs remain largely intact after complete spinal cord injury. We conclude that standing and locomotor recovery is due to the return of neuronal excitability within spinal sensorimotor circuits that do not require task-specific activity-dependent plasticity.

Descending Systems Direct Development of Key Spinal Motor Circuits.

The formation of mature spinal motor circuits is dependent on both activity-dependent and independent mechanisms during postnatal development. During this time, reorganization and refinement of spinal sensorimotor circuits occurs as supraspinal projections are integrated. However, specific features of postnatal spinal circuit development remain poorly understood. This study provides the first detailed characterization of rat spinal sensorimotor circuit development in the presence and absence of descending systems. We show that the development of proprioceptive afferent input to motoneurons (MNs) and Renshaw cells (RCs) is disrupted by thoracic spinal cord transection at postnatal day 5 (P5TX). P5TX also led to malformation of GABApre neuron axo-axonic contacts on Ia afferents and of the recurrent inhibitory circuit between MNs and RCs. Using a novel in situ perfused preparation for studying motor control, we show that malformation of these spinal circuits leads to hyperexcitability of the monosynaptic reflex. Our results demonstrate that removing descending input severely disrupts the development of spinal circuits and identifies key mechanisms contributing to motor dysfunction in conditions such as cerebral palsy and spinal cord injury.SIGNIFICANCE STATEMENT Acquisition of mature behavior during postnatal development correlates with the arrival and maturation of supraspinal projections to the spinal cord. However, we know little about the role that descending systems play in the maturation of spinal circuits. Here, we characterize postnatal development of key spinal microcircuits in the presence and absence of descending systems. We show that formation of these circuits is abnormal after early (postnatal day 5) removal of descending systems, inducing hyperexcitability of the monosynaptic reflex. The study is a detailed characterization of spinal circuit development elucidating how these mechanisms contribute to motor dysfunction in conditions such as cerebral palsy and spinal cord injury. Understanding these circuits is crucial to developing new therapeutics and improving existing ones in such conditions.

Top down control of spinal sensorimotor circuits essential for survival.

The ability to interact with challenging environments requires coordination of sensory and motor systems that underpin appropriate survival behaviours. All animals, including humans, use active and passive coping strategies to react to escapable or inescapable threats, respectively. Across species the neural pathways involved in survival behaviours are highly conserved and there is a consensus that knowledge of such pathways is a fundamental step towards understanding the neural circuits underpinning emotion in humans and treating anxiety or other prevalent emotional disorders. The midbrain periaqueductal grey (PAG) lies at the heart of the defence‐arousal system and its integrity is paramount to the expression of survival behaviours. To date, studies of ‘top down control’ components of defence behaviours have focused largely on the sensory and autonomic consequences of PAG activation. In this context, effects on motor activity have received comparatively little attention, despite overwhelming evidence of a pivotal role for the PAG in coordinating motor responses essential to survival (e.g. such as freezing in response to fear). In this article we provide an overview of top down control of sensory functions from the PAG, including selective control of different modalities of sensory, including proprioceptive, information forwarded to a major supsraspinal motor control centre, the cerebellum. Next, evidence from our own and other laboratories of PAG control of motor outflow is also discussed. Finally, the integration of sensorimotor functions by the PAG is considered, as part of coordinated defence behaviours that prepare an animal to be ready and able to react to danger.

A fuzzy controller for movement stabilization using afferent control: Controller synthesis and simulation

Stimulation of spinal sensorimotor circuits can improve motor control in animal models and humans with spinal cord injury (SCI). More recent evidence suggests that the stimulation increases the level of excitability in the spinal circuits, activates central pattern generators, and it is also able to recruit distinctive afferent pathways connected to specific sensorimotor circuits. In addition, the stimulation generates well-defined responses in leg muscles after each pulse. The problem is that in most of the neuromodulation devices, electrical stimulation parameters are regulated manually and stay constant during movement. Such a technique is likely suboptimal to intercede maximum therapeutic effects in patients. Therefore, in this article, a fuzzy controller has been designed to control limb kinematics during locomotion using the afferent control in a neuromechanical model without supraspinal drive simulating post-SCI situation. The proposed controller automatically tunes the weights of group Ia afferent inputs of the spinal cord to reset the phase appropriately during the reaction to an external perturbation. The kinematic motion data and weights of group Ia afferent inputs were the input and output of the controller, respectively. Simulation results showed the acceptable performance of the controller to establish adaptive locomotion against the perturbing forces based on the phase resetting of the walking rhythm.

Electrical maturation of spinal neurons in the human fetus: comparison of ventral and dorsal horn.

The spinal cord is critical for modifying and relaying sensory information to, and motor commands from, higher centers in the central nervous system to initiate and maintain contextually relevant locomotor responses. Our understanding of how spinal sensorimotor circuits are established during in utero development is based largely on studies in rodents. In contrast, there is little functional data on the development of sensory and motor systems in humans. Here, we use patch-clamp electrophysiology to examine the development of neuronal excitability in human fetal spinal cords (10-18 wk gestation; WG). Transverse spinal cord slices (300 μm thick) were prepared, and recordings were made, from visualized neurons in either the ventral (VH) or dorsal horn (DH) at 32°C. Action potentials (APs) could be elicited in VH neurons throughout the period examined, but only after 16 WG in DH neurons. At this age, VH neurons discharged multiple APs, whereas most DH neurons discharged single APs. In addition, at 16-18 WG, VH neurons also displayed larger AP and after-hyperpolarization amplitudes than DH neurons. Between 10 and 18 WG, the intrinsic properties of VH neurons changed markedly, with input resistance decreasing and AP and after-hyperpolarization amplitudes increasing. These findings are consistent with the hypothesis that VH motor circuitry matures more rapidly than the DH circuits that are involved in processing tactile and nociceptive information.

Closed-loop neuromodulation of spinal sensorimotor circuits controls refined locomotion after complete spinal cord injury.

Neuromodulation of spinal sensorimotor circuits improves motor control in animal models and humans with spinal cord injury. With common neuromodulation devices, electrical stimulation parameters are tuned manually and remain constant during movement. We developed a mechanistic framework to optimize neuromodulation in real time to achieve high-fidelity control of leg kinematics during locomotion in rats. We first uncovered relationships between neuromodulation parameters and recruitment of distinct sensorimotor circuits, resulting in predictive adjustments of leg kinematics. Second, we established a technological platform with embedded control policies that integrated robust movement feedback and feed-forward control loops in real time. These developments allowed us to conceive a neuroprosthetic system that controlled a broad range of foot trajectories during continuous locomotion in paralyzed rats. Animals with complete spinal cord injury performed more than 1000 successive steps without failure, and were able to climb staircases of various heights and lengths with precision and fluidity. Beyond therapeutic potential, these findings provide a conceptual and technical framework to personalize neuromodulation treatments for other neurological disorders.

Selective corticospinal tract injury in the rat induces primary afferent fiber sprouting in the spinal cord and hyperreflexia.

The corticospinal tract (CST) has dense contralateral and sparse ipsilateral spinal cord projections that converge with proprioceptive afferents on common spinal targets. Previous studies in adult rats indicate that the loss of dense contralateral spinal CST connections after unilateral pyramidal tract section (PTx), which models CST loss after stroke or spinal cord injury, leads to outgrowth from the spared side into the affected, ipsilateral, spinal cord. The reaction of proprioceptive afferents after this CST injury, however, is not known. Knowledge of proprioceptive afferent responses after loss of the CST could inform mechanisms of maladaptive plasticity in spinal sensorimotor circuits after injury. Here, we hypothesize that the loss of the contralateral CST results in a reactive increase in muscle afferents from the impaired limb and enhancement of their physiological actions within the cervical spinal cord. We found that 10 d after PTx, proprioceptive afferents sprout into cervical gray matter regions denervated by the loss of CST terminations. Furthermore, VGlut1-positive boutons, indicative of group 1A afferent terminals, increased on motoneurons. PTx also produced an increase in microglial density within the gray matter regions where CST terminations were lost. These anatomical changes were paralleled by reduction in frequency-dependent depression of the H-reflex, suggesting hyperreflexia. Our data demonstrate for the first time that selective CST injury induces maladaptive afferent fiber plasticity remote from the lesion. Our findings suggest a novel structural reaction of proprioceptive afferents to the loss of CST terminations and provide insight into mechanisms underlying spasticity.

An update on the pathophysiology and genetics of restless legs syndrome

This update on restless legs syndrome (RLS) focuses on its pathophysiology, genetics, health impact, and treatment. Although symptoms are exquisitely responsive to dopaminergics, clear delineation of dopaminergic pathology has not emerged. Rather, heuristic models of alterations in spinal sensorimotor circuits and central nervous system iron deficiency are gaining more attention. Genome-wide association studies have recently identified polymorphisms in three genes with no obvious relationship to dopamine that account for 70% of the population risk for RLS. A single variant in the BTBD9 gene on chromosome 6 contributes to 50% of the population risk. Although the functions of BTBD9 remain uncertain, its biological plausibility is evidenced by its dose-dependent relationship to periodic limb movements of sleep, decrements in iron stores, and ethnic differences in RLS prevalence. RLS is also implicated in cardiovascular morbidity. Despite these advances in our knowledge, there remain unanswered questions about the pathophysiology of RLS as well as its genetics, health-related significance, and treatment.

Spatial encoding in spinal sensorimotor circuits differs in different wild type mice strains

BackgroundPrevious studies in the rat have shown that the spatial organisation of the receptive fields of nociceptive withdrawal reflex (NWR) system are functionally adapted through experience dependent mechanisms, termed somatosensory imprinting, during postnatal development. Here we wanted to clarify 1) if mice exhibit a similar spatial encoding of sensory input to NWR as previously found in the rat and 2) if mice strains with a poor learning capacity in various behavioural tests, associated with deficient long term potention, also exhibit poor adaptation of NWR.The organisation of the NWR system in two adult wild type mouse strains with normal long term potentiation (LTP) in hippocampus and two adult wild type mouse strains exhibiting deficiencies in corresponding LTP were used and compared to previous results in the rat. Receptive fields of reflexes in single hindlimb muscles were mapped with CO2 laser heat pulses.ResultsWhile the spatial organisation of the nociceptive receptive fields in mice with normal LTP were very similar to those in rats, the LTP impaired strains exhibited receptive fields of NWRs with aberrant sensitivity distributions. However, no difference was found in NWR thresholds or onset C-fibre latencies suggesting that the mechanisms determining general reflex sensitivity and somatosensory imprinting are different.ConclusionOur results thus confirm that sensory encoding in mice and rat NWR is similar, provided that mice strains with a good learning capability are studied and raise the possibility that LTP like mechanisms are involved in somatosensory imprinting.